Osteopontin as a potential molecular target for ovarian clear cell carcinoma therapy.

Abstract

e15550 Background: Recent studies have demonstrated overexpression of osteopontin (OPN) in ovarian clear cell carcinoma (OCCC) and poor prognosis in OCCC is associated with the expression of OPN. In this study, we revealed the role of OPN in invasiveness and the effects of statin, a family of 3-hydroxy-3-methylglutaryl CoA reductase inhibitors, on OCCC cells in vitro and in vivo. Methods: Ovarian clear cell carcinoma cell lines, RMG-1 and TOV-21G, were used to monitor changes in OPN levels, and cell invasiveness following treatment with OPN, statin, and transfection with siRNA. Changes in OPN gene expression were determined by real-time RT-PCR. Invasion assay and MTT assay were performed to determine effects on cell invasiveness and proliferation. A xenograft tumor model was constructed to evaluate the effects of statin (15-mg/kg/day) on cell proliferation and apoptosis in vivo. Results: The OPN gene expressions in OCCC cell lines were higher than in serous and mucinous adenocarcinoma cell lines. Invasion assays indicated that OPN (0.6µM) enhanced in vitro extracellular matrix (ECM) invasion in RMG-1 (3-fold) and TOV-21G (3.1-fold), respectively. Statin (4µM) reduced expression of OPN (RMG-1: 1.3-fold, and TOV-21G: 1.2-fold), and decreased ECM invasion (RMG-1: 1.3-fold, and TOV-21G: 1.7-fold). RNA interference also suppressed ECM invasion in RMG-1 (1.7-fold) and TOV-21G (1.5-fold), respectively. Statin inhibited OCCC cell proliferation, and the inhibition rate was approximately 40% to 50% after treatment with statin (10µM) for 48 h. In the xenograft studies, statin treatment resulted in a significant growth inhibition. Furthermore, the mice treated with statin survived significantly longer compared to the saline-treated group. Whereas every mouse died within 80 days in the saline-treated group, the 90-day survival rate was 66.7% in the statin-treated group. Apoptosis was increased in statin-treated mice in comparison to saline-treated group. Conclusions: We demonstrated that down-regulation of OPN reduced cell invasiveness in OCCC cells. Our results suggest that anticancer effects of statin may contribute to OCCC inhibition, and OPN may be a potential molecular target for OCCC therapy.